Abstract for presentation at 11th International Congress of Human Genetics

Clinical appreciation of relatedness between syndromes often reflects underlying aetiological similarities as well. Disorders caused by clustered, gain-of-function mutations in the genes encoding filamins – filaminopathies- are a case in point. Phenotypic similarities between the otopalatodigital syndrome spectrum disorders, caused by mutations in the X linked gene FLNA, and Larsen syndrome and atelosteogenesis types 1 and 3, caused by mutations within the paralogous gene, FLNB, have long been appreciated. Only recently has the description of the distribution of mutations underlying these disorders provided an explanation for their relatedness at a clinical level. Filamins are proteins that cross-link the actin cytoskeleton and mediate diverse cellular functions such as mechanoprotection, modulation of primary and secondary messenger activity during signal transduction and regulation of transcriptional activity. The multiplicity of functions is reflected in the large number (>40) of known binding partners of filamins. Loss-of-function phenotypes for the filamin related conditions lead to significantly different clinical phenotypes suggesting that the filaminopathies as a group are mediated by alteration of specific filamin-mediated functions. Identifying the specific processes that are altered to lead to these clinical phenotypes poses a significant problem in the face of such biochemical complexity but close study of clinical phenotypes is once again presenting opportunities to resolve the pathways that are disturbed to lead to defective morphogenesis in these conditions.